Bridging animal and human models of exercise-induced brain plasticity

Abstract

Significant progress has been made in understanding the neurobiological mechanisms through which exercise protects and restores the brain. In this feature review, we integrate animal and human research, examining physical activity effects across multiple levels of description (neurons up to inter-regional pathways). We evaluate the influence of exercise on hippocampal structure and function, addressing common themes such as spatial memory and pattern separation, brain structure and plasticity, neurotrophic factors, and vasculature. Areas of research focused more within species, such as hippocampal neurogenesis in rodents, also provide crucial insight into the protective role of physical activity. Overall, converging evidence suggests exercise benefits brain function and cognition across the mammalian lifespan, which may translate into reduced risk for Alzheimer's disease (AD) in humans.

Figure 1

Exercise increases the production of new neurons in the dentate gyrus (DG) of the hippocampus. In two independent studies [18,19], mice were housed under (A,I) control (CON), (B,J) enriched environment only (EEO), (C,K) running (RUN), or (D,L) enriched environment and running (EER) conditions in (A–D) single or (I–L) group housing. Confocal images of bromodeoxyuridine (BrdU)-positive cells in the DG in sections derived from mice housed under (E) CON, (F) EEO (G) RUN, and (H) EER conditions. Sections were immunofluorescently double-labeled for BrdU (green) and NeuN (red) indicating neuronal phenotype (adapted from [18]). Panels (A–D) are reproduced with permission from [19]. Both studies show that adult DG neurogenesis is increased under the RUN and EER conditions but not under CON or EEO, indicating that running is the neurogenic stimulus.

Figure 2

In search of the neurobiological mechanisms mediating physical activity benefits on cognition, behavior, and neurodegenerative diseases. Physical activity influences both the peripheral nervous system and the central nervous system (CNS), which interact with each other in a bidirectional manner. Animal models provide a means to measure the effects of physical activity directly and at a microscale, whereas human studies mostly depend on noninvasive neuroimaging methods that measure biomarkers of cellular and molecular processes at a macroscale. There may be opportunities to bridge between animal and human measures with conceptually parallel experimental designs that assess the relationship between the effects of physical activity on central and peripherally measured outcomes and/or utilize analogous imaging methods to measure CNS outcomes. Ultimately, understanding the neurobiological mechanisms that mediate the effects of physical activity on human behavior and disease will improve public health recommendations that outline what types of physical activity produce the most neuroprotection and real-world benefit. It will also provide insight how this varies across the lifespan, different genetic profiles and neurodegenerative disorders. Abbreviations: BDNF, brain-derived neurotrophic factor; TrkB, tropomyosin receptor kinase B; LTP, long-term potentiation; LTD, long-term depression; DWI, diffusion-weighted imaging; MRS, magnetic resonance spectroscopy; ASL, arterial spin labeling; MRA, magnetic resonance angiography; fMRI, functional MRI; BOLD, blood oxygen level dependent; TMS, transcranial magnetic stimulation; EEG/ERP, electroencephalography/event-related potentials; IGF-1, insulin-like growth factor 1; VEGF, vascular endothelial growth factor; CRP, C-reactive protein; SNP, single-nucleotide polymorphism.